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</svg> Books</a></div><div class="jr-rhead f1 flexh"><div class="head"></div><div class="body"><div class="t">Childhood Pheochromocytoma and Paraganglioma Treatment (PDQ®): Health Professional Version</div><div class="j">PDQ Cancer Information Summaries [Internet]</div></div><div class="tail"></div></div><div id="jr-tb2"><a id="jr-bkhelp-sw" class="btn wsprkl hidden" title="Help with NLM PubReader">?</a><a id="jr-help-sw" class="btn wsprkl hidden" title="Settings and typography in NLM PubReader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 512 512" preserveAspectRatio="none"><path d="M462,283.742v-55.485l-29.981-10.662c-11.431-4.065-20.628-12.794-25.274-24.001 c-0.002-0.004-0.004-0.009-0.006-0.013c-4.659-11.235-4.333-23.918,0.889-34.903l13.653-28.724l-39.234-39.234l-28.72,13.652 c-10.979,5.219-23.68,5.546-34.908,0.889c-0.005-0.002-0.01-0.003-0.014-0.005c-11.215-4.65-19.933-13.834-24-25.273L283.741,50 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id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK552286_"><span class="title" itemprop="name">Childhood Pheochromocytoma and Paraganglioma Treatment (PDQ®)</span></h1><div class="subtitle whole_rhythm">Health Professional Version</div><p class="contribs">PDQ Pediatric Treatment Editorial Board.</p><p class="fm-aai"><a href="#_NBK552286_pubdet_">Publication Details</a></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="_abs_rndgid_" itemprop="description"><p id="CDR0000800108__1556">This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of pediatric pheochromocytoma and paraganglioma. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.</p><p id="CDR0000800108__1557">This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).</p></div><div id="CDR0000800108__2266"><h2 id="_CDR0000800108__2266_">Incidence</h2><p id="CDR0000800108__2267">Pheochromocytoma and paraganglioma are rare catecholamine-producing tumors with a combined annual incidence of three cases per 1 million individuals. These tumors are also rare in the pediatric and adolescent population, accounting for approximately 20% of all cases.[<a class="bibr" href="#CDR0000800108_rl_2266_1" rid="CDR0000800108_rl_2266_1">1</a>,<a class="bibr" href="#CDR0000800108_rl_2266_2" rid="CDR0000800108_rl_2266_2">2</a>]</p><div id="CDR0000800108_rl_2266"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000800108_rl_2266_1">Barontini M, Levin G, Sanso G: Characteristics of pheochromocytoma in a 4- to 20-year-old population. Ann N Y Acad Sci 1073: 30-7, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/17102069" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17102069</span></a>]</div></li><li><div class="bk_ref" id="CDR0000800108_rl_2266_2">King KS, Prodanov T, Kantorovich V, et al.: Metastatic pheochromocytoma/paraganglioma related to primary tumor development in childhood or adolescence: significant link to SDHB mutations. J Clin Oncol 29 (31): 4137-42, 2011. [<a href="/pmc/articles/PMC3208535/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3208535</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21969497" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21969497</span></a>]</div></li></ol></div></div><div id="CDR0000800108__2268"><h2 id="_CDR0000800108__2268_">Anatomy</h2><p id="CDR0000800108__2269">Tumors arising within the adrenal gland are known as pheochromocytomas, whereas morphologically identical tumors arising elsewhere are termed paragangliomas. Paragangliomas are further divided into the following subtypes:[<a class="bibr" href="#CDR0000800108_rl_2268_1" rid="CDR0000800108_rl_2268_1">1</a>,<a class="bibr" href="#CDR0000800108_rl_2268_2" rid="CDR0000800108_rl_2268_2">2</a>]</p><ul id="CDR0000800108__2270"><li class="half_rhythm"><div>Sympathetic paragangliomas that predominantly arise from the intra-abdominal sympathetic trunk and usually produce catecholamines.</div></li><li class="half_rhythm"><div>Parasympathetic paragangliomas that are distributed along the parasympathetic nerves of the head, neck, and mediastinum and are rarely functional.</div></li></ul><div id="CDR0000800108_rl_2268"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000800108_rl_2268_1">Lenders JW, Eisenhofer G, Mannelli M, et al.: Phaeochromocytoma. Lancet 366 (9486): 665-75, 2005 Aug 20-26. [<a href="https://pubmed.ncbi.nlm.nih.gov/16112304" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16112304</span></a>]</div></li><li><div class="bk_ref" id="CDR0000800108_rl_2268_2">Waguespack SG, Rich T, Grubbs E, et al.: A current review of the etiology, diagnosis, and treatment of pediatric pheochromocytoma and paraganglioma. J Clin Endocrinol Metab 95 (5): 2023-37, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20215394" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20215394</span></a>]</div></li></ol></div></div><div id="CDR0000800108__2392"><h2 id="_CDR0000800108__2392_">Molecular Characterization of Pheochromocytoma and Paraganglioma</h2><p id="CDR0000800108__2393">Comprehensive molecular profiling of 173 cases of pheochromocytomas and paragangliomas (mean age at diagnosis, 47 years) identified three well-defined molecular subgroups: pseudohypoxia-related clusters 1A and 1B, kinase signaling–related cluster 2, and WNT signaling–related cluster 3.[<a class="bibr" href="#CDR0000800108_rl_2392_1" rid="CDR0000800108_rl_2392_1">1</a>] About 70% of patients with pheochromocytoma and paraganglioma can be assigned to one of these clusters. Each cluster has unique clinical, biochemical, and imaging characteristics that may help guide the treatment and follow-up of patients.[<a class="bibr" href="#CDR0000800108_rl_2392_2" rid="CDR0000800108_rl_2392_2">2</a>,<a class="bibr" href="#CDR0000800108_rl_2392_3" rid="CDR0000800108_rl_2392_3">3</a>]</p><ul id="CDR0000800108__2394"><li class="half_rhythm"><div><b>Cluster 1:</b> These tumors account for about 25% to 35% of paragangliomas and pheochromocytomas, are usually extra-adrenal, and tend to have a noradrenergic biochemical phenotype because these tumors lack the enzyme phenylethanolamine N-methyltransferase, which converts norepinephrine to epinephrine.[<a class="bibr" href="#CDR0000800108_rl_2392_3" rid="CDR0000800108_rl_2392_3">3</a>,<a class="bibr" href="#CDR0000800108_rl_2392_4" rid="CDR0000800108_rl_2392_4">4</a>] Variants in this cluster stabilize HIF-2 alpha and promote angiogenesis and tumor progression. Patients with tumors in this cluster present at a younger age, especially those with <i>SDHB</i> variants (<20 years). Clinically, these patients have sustained hypertension. Patients with cluster 1 tumors develop multiple and recurrent tumors that have the potential for metastatic spread, particularly for patients with <i>SDHA</i> and <i>SDHB</i> variants. With a median follow-up of 5 years, 3 of 30 asymptomatic children (10%) who were carriers of an <i>SDHB</i> variant developed abdominal paragangliomas identified on surveillance imaging. This cluster can be further subdivided into clusters 1A and 1B, as described below.[<a class="bibr" href="#CDR0000800108_rl_2392_5" rid="CDR0000800108_rl_2392_5">5</a>]<ul id="CDR0000800108__2395"><li class="half_rhythm"><div><b>Cluster 1A</b> tumors have variants in the Krebs cycle–associated genes <i>SDHA</i> (<i>AF2</i>), <i>SDHB</i>, <i>SDHC</i>, <i>SDHD</i>, <i>FH</i>, <i>MDH2</i>, <i>IDH1</i>, <i>IDH2</i>, <i>GOT2</i>, <i>SLC25A11</i>, and <i>DLST</i>. Most of these are germline pathogenic variants and have a higher metastatic risk.[<a class="bibr" href="#CDR0000800108_rl_2392_5" rid="CDR0000800108_rl_2392_5">5</a>]</div></li><li class="half_rhythm"><div><b>Cluster 1B</b> tumors have variants in <i>VHL</i>- and <i>EPAS1</i>-related genes such as <i>EGLN2</i>, <i>EGLN1</i>, <i>VHL</i>, <i>EPAS1</i>, and <i>ACO1</i>. About 25% of these are germline pathogenic variants.[<a class="bibr" href="#CDR0000800108_rl_2392_5" rid="CDR0000800108_rl_2392_5">5</a>]</div></li></ul></div></li><li class="half_rhythm"><div><b>Cluster 2:</b> These tumors usually arise in the adrenal gland and have an adrenergic biochemical phenotype. Cluster 2 tumors affect older patients, with a peak age of 40 years for clinical manifestations. Clinically, they present with an intermittent catecholamine secretion pattern. This cluster includes variants in tyrosine kinases, including <i>RET</i>, <i>NF1</i>, <i>HRAS</i>, <i>TMEM127</i>, <i>MAX</i>, and <i>FGFR1</i>.[<a class="bibr" href="#CDR0000800108_rl_2392_5" rid="CDR0000800108_rl_2392_5">5</a>]</div></li><li class="half_rhythm"><div><b>Cluster 3:</b> These tumors have somatic variants of the WNT signaling pathway, which includes variants in the <i>CSDE1</i> gene and <i>MAML3</i> gene fusions. These variants are associated with an aggressive clinical course. Cluster 3 tumors are located mainly in the adrenal gland and account for 5% to 10% of all pheochromocytomas and paragangliomas. They have an intermediate metastatic risk and can secrete normetanephrine and metanephrines. Genomic alterations in this cluster are somatic.[<a class="bibr" href="#CDR0000800108_rl_2392_5" rid="CDR0000800108_rl_2392_5">5</a>]</div></li></ul><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figCDR00008001082400"><a href="/books/NBK552286/table/CDR0000800108__2400/?report=objectonly" target="object" title="Table" class="img_link icnblk_img" rid-ob="figobCDR00008001082400"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="CDR0000800108__2400"><a href="/books/NBK552286/table/CDR0000800108__2400/?report=objectonly" target="object" rid-ob="figobCDR00008001082400">Table</a></h4><p class="float-caption no_bottom_margin">Table 1. Molecular Subgroups of Pheochromocytoma and Paraganglioma. </p></div></div><div id="CDR0000800108_rl_2392"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000800108_rl_2392_1">Fishbein L, Leshchiner I, Walter V, et al.: Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma. Cancer Cell 31 (2): 181-193, 2017. [<a href="/pmc/articles/PMC5643159/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5643159</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/28162975" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28162975</span></a>]</div></li><li><div class="bk_ref" id="CDR0000800108_rl_2392_2">Nölting S, Bechmann N, Taieb D, et al.: Personalized Management of Pheochromocytoma and Paraganglioma. Endocr Rev 43 (2): 199-239, 2022. [<a href="/pmc/articles/PMC8905338/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC8905338</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/34147030" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 34147030</span></a>]</div></li><li><div class="bk_ref" id="CDR0000800108_rl_2392_3">Crona J, Taïeb D, Pacak K: New Perspectives on Pheochromocytoma and Paraganglioma: Toward a Molecular Classification. Endocr Rev 38 (6): 489-515, 2017. [<a href="/pmc/articles/PMC5716829/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5716829</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/28938417" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28938417</span></a>]</div></li><li><div class="bk_ref" id="CDR0000800108_rl_2392_4">Nölting S, Ullrich M, Pietzsch J, et al.: Current Management of Pheochromocytoma/Paraganglioma: A Guide for the Practicing Clinician in the Era of Precision Medicine. Cancers (Basel) 11 (10): , 2019. [<a href="/pmc/articles/PMC6827093/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6827093</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/31597347" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31597347</span></a>]</div></li><li><div class="bk_ref" id="CDR0000800108_rl_2392_5">Alrezk R, Suarez A, Tena I, et al.: Update of Pheochromocytoma Syndromes: Genetics, Biochemical Evaluation, and Imaging. Front Endocrinol (Lausanne) 9: 515, 2018. [<a href="/pmc/articles/PMC6277481/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6277481</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/30538672" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30538672</span></a>]</div></li></ol></div></div><div id="CDR0000800108__865"><h2 id="_CDR0000800108__865_">Genetic Factors and Syndromes Associated With Pheochromocytoma and Paraganglioma</h2><p id="CDR0000800108__866">Up to 30% of all pheochromocytomas and paragangliomas are estimated to be familial, and several susceptibility genes have been described (see <a href="/books/NBK552286/table/CDR0000800108__887/?report=objectonly" target="object" rid-ob="figobCDR0000800108887">Table 2</a>). The median age at presentation in most familial syndromes is 30 to 35 years, and up to 50% of patients have the disease by age 26 years.[<a class="bibr" href="#CDR0000800108_rl_865_1" rid="CDR0000800108_rl_865_1">1</a>-<a class="bibr" href="#CDR0000800108_rl_865_4" rid="CDR0000800108_rl_865_4">4</a>]</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figCDR0000800108887"><a href="/books/NBK552286/table/CDR0000800108__887/?report=objectonly" target="object" title="Table" class="img_link icnblk_img" rid-ob="figobCDR0000800108887"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="CDR0000800108__887"><a href="/books/NBK552286/table/CDR0000800108__887/?report=objectonly" target="object" rid-ob="figobCDR0000800108887">Table</a></h4><p class="float-caption no_bottom_margin">Table 2. Characteristics of Paraganglioma (PGL) and Pheochromocytoma (PCC) Associated With Susceptibility Genes<sup>a</sup>. </p></div></div><p id="CDR0000800108__1304">Genetic factors and syndromes associated with an increased risk of pheochromocytoma and paraganglioma include the following:</p><ol id="CDR0000800108__867"><li class="half_rhythm"><div class="half_rhythm"><b>von Hippel-Lindau (VHL) disease:</b> Pheochromocytoma and paraganglioma occur in 10% to 20% of patients with VHL. For more information, see <a href="/books/n/pdqcis/CDR0000803496/?report=reader">Von Hippel-Lindau Disease</a>.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Multiple endocrine neoplasia (MEN) syndrome type 2:</b> Codon-specific variants of the <i>RET</i> gene are associated with a 50% risk of development of pheochromocytoma in individuals with MEN2A and MEN2B. Somatic <i>RET</i> variants are also found in those with sporadic pheochromocytoma and paraganglioma.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Neurofibromatosis type 1 (NF1):</b> Pheochromocytoma and paraganglioma are a rare occurrence in patients with NF1. They typically have characteristics similar to those of sporadic tumors, with a relatively late mean age of onset and rarity in pediatrics.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Familial pheochromocytoma/paraganglioma syndromes:</b> These syndromes are commonly caused by pathogenic variants in <i>SDHA</i>, <i>SDHB</i>, <i>SDHC</i>, and <i>SDHD</i> and are inherited in an autosomal dominant manner. Pathogenic <i>SDHB</i> variants are the most common, followed by <i>SDHD</i>, <i>SDHC</i>, and <i>SDHA</i>. Other genes implicated in this syndrome include <i>SDHAF2</i>, <i>TMEM127</i>, <i>FH</i>, and <i>MAX</i>. </div><div class="half_rhythm">Tumors from patients with <i>SDHB</i> and <i>SDHC</i> variants mainly arise in extra-adrenal locations, whereas tumors from patients with <i>SDHD</i> variants are mainly found in the head and neck area. <i>SDHA</i> variants are linked to sympathetic and parasympathetic paragangliomas. For more information, see <a href="/books/NBK552286/table/CDR0000800108__887/?report=objectonly" target="object" rid-ob="figobCDR0000800108887">Table 2</a>.</div><div class="half_rhythm">For more information, see the <a href="/books/n/pdqcis/CDR0000062890/?report=reader#CDR0000062890__850">Familial Pheochromocytoma and Paraganglioma Syndrome</a> section in Genetics of Endocrine and Neuroendocrine Neoplasias.</div></li><li class="half_rhythm"><div class="half_rhythm">
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<b>Other syndromes:</b>
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<ul id="CDR0000800108__869"><li class="half_rhythm"><div><b>Carney triad syndrome:</b> This condition includes three tumors: paraganglioma, gastrointestinal stromal tumor (GIST), and pulmonary chondromas. Pheochromocytomas and other lesions, such as esophageal leiomyomas and adrenocortical adenomas, have also been described. The syndrome primarily affects young women, with a mean age of 21 years at time of presentation. Approximately one-half of patients present with paraganglioma or pheochromocytoma, although multiple lesions occur in approximately 20% of the cases. About 20% of patients have all three tumor types; the remainder have two of the three, most commonly GIST and pulmonary chondromas. This triad doesn’t appear to run in families. However, approximately 10% of patients have germline pathogenic variants in the <i>SDHA</i>, <i>SDHB</i>, or <i>SDHC</i> genes.[<a class="bibr" href="#CDR0000800108_rl_865_5" rid="CDR0000800108_rl_865_5">5</a>,<a class="bibr" href="#CDR0000800108_rl_865_6" rid="CDR0000800108_rl_865_6">6</a>]</div></li><li class="half_rhythm"><div><b>Carney-Stratakis syndrome:</b> Also called Carney dyad syndrome, this condition includes paraganglioma and GIST but not pulmonary chondromas. It is inherited in an autosomal dominant manner with incomplete penetrance. It is equally common in men and women, with an average age of 23 years at presentation. Most patients with this syndrome have been found to carry germline pathogenic variants in the <i>SDHB</i>, <i>SDHC</i>, or <i>SDHD</i> genes.[<a class="bibr" href="#CDR0000800108_rl_865_6" rid="CDR0000800108_rl_865_6">6</a>] For more information, see <a href="/books/n/pdqcis/CDR0000062890/?report=reader">Genetics of Endocrine and Neuroendocrine Neoplasias</a>.</div></li><li class="half_rhythm"><div><b>Pacak-Zhuang syndrome:</b> This syndrome results from somatic gain-of-function variants in the hypoxia-inducible factor 2 alpha (HIF-2 alpha) protein, which is encoded by the <i>EPAS1</i> gene. This syndrome is characterized by congenital polycythemia, multiple paragangliomas, and duodenal somatostatinomas.[<a class="bibr" href="#CDR0000800108_rl_865_7" rid="CDR0000800108_rl_865_7">7</a>] One patient with Pacak-Zhuang syndrome was treated with belzutifan, a potent and selective small-molecule inhibitor of the HIF-2 alpha protein. This treatment led to a rapid and sustained tumor response, along with a resolution of hypertension, headaches, and long-standing polycythemia.[<a class="bibr" href="#CDR0000800108_rl_865_8" rid="CDR0000800108_rl_865_8">8</a>]</div></li></ul>
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</div></li></ol><div id="CDR0000800108_rl_865"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000800108_rl_865_1">Welander J, Söderkvist P, Gimm O: Genetics and clinical characteristics of hereditary pheochromocytomas and paragangliomas. Endocr Relat Cancer 18 (6): R253-76, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/22041710" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22041710</span></a>]</div></li><li><div class="bk_ref" id="CDR0000800108_rl_865_2">Timmers HJ, Gimenez-Roqueplo AP, Mannelli M, et al.: Clinical aspects of SDHx-related pheochromocytoma and paraganglioma. Endocr Relat Cancer 16 (2): 391-400, 2009. [<a href="/pmc/articles/PMC4711350/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4711350</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19190077" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19190077</span></a>]</div></li><li><div class="bk_ref" id="CDR0000800108_rl_865_3">Ricketts CJ, Forman JR, Rattenberry E, et al.: Tumor risks and genotype-phenotype-proteotype analysis in 358 patients with germline mutations in SDHB and SDHD. Hum Mutat 31 (1): 41-51, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/19802898" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19802898</span></a>]</div></li><li><div class="bk_ref" id="CDR0000800108_rl_865_4">Burnichon N, Cascón A, Schiavi F, et al.: MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma. Clin Cancer Res 18 (10): 2828-37, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/22452945" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22452945</span></a>]</div></li><li><div class="bk_ref" id="CDR0000800108_rl_865_5">Boikos SA, Xekouki P, Fumagalli E, et al.: Carney triad can be (rarely) associated with germline succinate dehydrogenase defects. Eur J Hum Genet 24 (4): 569-73, 2016. [<a href="/pmc/articles/PMC4929866/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4929866</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26173966" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26173966</span></a>]</div></li><li><div class="bk_ref" id="CDR0000800108_rl_865_6">Stratakis CA, Carney JA: The triad of paragangliomas, gastric stromal tumours and pulmonary chondromas (Carney triad), and the dyad of paragangliomas and gastric stromal sarcomas (Carney-Stratakis syndrome): molecular genetics and clinical implications. J Intern Med 266 (1): 43-52, 2009. [<a href="/pmc/articles/PMC3129547/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3129547</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19522824" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19522824</span></a>]</div></li><li><div class="bk_ref" id="CDR0000800108_rl_865_7">Abdallah A, Pappo A, Reiss U, et al.: Clinical manifestations of Pacak-Zhuang syndrome in a male pediatric patient. Pediatr Blood Cancer 67 (4): e28096, 2020. [<a href="/pmc/articles/PMC7036331/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7036331</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/31876082" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31876082</span></a>]</div></li><li><div class="bk_ref" id="CDR0000800108_rl_865_8">Kamihara J, Hamilton KV, Pollard JA, et al.: Belzutifan, a Potent HIF2α Inhibitor, in the Pacak-Zhuang Syndrome. N Engl J Med 385 (22): 2059-2065, 2021. [<a href="/pmc/articles/PMC11245359/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC11245359</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/34818480" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 34818480</span></a>]</div></li></ol></div></div><div id="CDR0000800108__873"><h2 id="_CDR0000800108__873_">Correlation Between Clinical and Molecular Features</h2><p id="CDR0000800108__1307">Studies of germline variants in young patients with pheochromocytoma or paraganglioma have shown that these patients have a high prevalence (70%–80%) of germline pathogenic variants and have further characterized this group of neoplasms, as follows:</p><ol id="CDR0000800108__1308"><li class="half_rhythm"><div class="half_rhythm"> In a study of 49 patients younger than 20 years with a paraganglioma or pheochromocytoma, 39 (79%) had an underlying germline pathogenic variant that involved the <i>SDHB</i> (n = 27; 55%), <i>SDHD</i> (n = 4; 8%), <i>VHL</i> (n = 6; 12%), or <i>NF1</i> (n = 2; 4%) gene.[<a class="bibr" href="#CDR0000800108_rl_873_1" rid="CDR0000800108_rl_873_1">1</a>] The incidence and type of variant correlated with the site and extent of disease.<ul id="CDR0000800108__1309"><li class="half_rhythm"><div>The germline pathogenic variant rates for patients with nonmetastatic disease were lower than those observed in patients who had evidence of metastases (64% vs. 87.5%). </div></li><li class="half_rhythm"><div>Among patients with metastatic disease, the incidence of <i>SDHB</i> variants was high (72%), and most presented with disease in the retroperitoneum. Five patients died of their disease.</div></li><li class="half_rhythm"><div>All patients with <i>SDHD</i> variants had head and neck primary tumors.</div></li></ul></div></li><li class="half_rhythm"><div class="half_rhythm">In another study, the incidence of germline pathogenic variants involving <i>RET</i>, <i>VHL</i>, <i>SDHD</i>, and <i>SDHB</i> in patients with nonsyndromic paraganglioma was 70% for patients younger than 10 years and 51% among those aged 10 to 20 years.[<a class="bibr" href="#CDR0000800108_rl_873_2" rid="CDR0000800108_rl_873_2">2</a>] In contrast, only 16% of patients older than 20 years had an identifiable variant. </div><div class="half_rhythm">It is important to note that these two studies did not include systematic screening for other genes that have been recently described in paraganglioma and pheochromocytoma syndromes, such as <i>KIF1B</i>, <i>EGLN1</i>, <i>TMEM127</i>, <i>SDHA</i>, and <i>MAX</i> (see <a href="/books/NBK552286/table/CDR0000800108__887/?report=objectonly" target="object" rid-ob="figobCDR0000800108887">Table 2</a>).</div></li><li class="half_rhythm"><div class="half_rhythm">In a retrospective review of 55 patients younger than 21 years referred to the National Cancer Institute, 80% of patients had a germline pathogenic variant.[<a class="bibr" href="#CDR0000800108_rl_873_3" rid="CDR0000800108_rl_873_3">3</a>] <ul id="CDR0000800108__2111"><li class="half_rhythm"><div>Most patients were found to have either the <i>VHL</i> (38%) or the <i>SDHB</i> (25%) variant. Pheochromocytoma was present in 67% of the patients (37 of 55) and was bilateral in 51% of patients (19 of 37).</div></li><li class="half_rhythm"><div>Most patients with bilateral pheochromocytomas had <i>VHL</i> variants (79%).</div></li></ul></div></li><li class="half_rhythm"><div class="half_rhythm">Similarly, in a study of 88 children with pheochromocytoma and paraganglioma identified in the German Pediatric Oncology Hematology–Malignant Endocrine Tumor registry, the following was observed:[<a class="bibr" href="#CDR0000800108_rl_873_4" rid="CDR0000800108_rl_873_4">4</a>]<ul id="CDR0000800108__2398"><li class="half_rhythm"><div>Pathogenic variant screening from 66 patients revealed that 96% of the variants were confined to the pseudohypoxia cluster (66% affecting the <i>VHL</i> and <i>EPAS1</i> genes and 33% affecting the <i>SDHB</i> and <i>SDHD</i> genes). </div></li><li class="half_rhythm"><div>In this analysis, extent of resection was a significant prognostic factor for disease-free survival.</div></li></ul></div></li><li class="half_rhythm"><div class="half_rhythm">A retrospective analysis from the European-American-Asian-Pheochromocytoma-Paraganglioma-Registry identified 177 patients with paraganglial tumors who were diagnosed before age 18 years.[<a class="bibr" href="#CDR0000800108_rl_873_5" rid="CDR0000800108_rl_873_5">5</a>][<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000810035/" class="def">Level of evidence C1</a>] <ul id="CDR0000800108__1311"><li class="half_rhythm"><div>Eighty percent of registrants had germline pathogenic variants (49% with <i>VHL</i>, 15% with <i>SDHB</i>, 10% with <i>SDHD</i>, 4% with <i>NF1</i>, and one patient each with <i>RET</i>, <i>SDHA</i>, and <i>SDHC</i>).</div></li><li class="half_rhythm"><div>A second primary paraganglial tumor developed in 38% of patients, with increasing frequency over time, reaching 50% at 30 years from initial presentation.</div></li><li class="half_rhythm"><div>Prevalence of second tumors was higher in patients with hereditary disease. Sixteen patients (9%) with hereditary disease had malignant tumors, ten at initial presentation and another six during follow-up. Malignancy was associated with <i>SDHB</i> variants. Eight patients (5%) died, all of whom had a germline pathogenic variant. Mean life expectancy was 62 years for patients with hereditary disease.</div></li></ul></div></li><li class="half_rhythm"><div class="half_rhythm">A large retrospective review from tertiary medical centers identified 95 of 748 patients whose tumors first presented in childhood.[<a class="bibr" href="#CDR0000800108_rl_873_6" rid="CDR0000800108_rl_873_6">6</a>]<ul id="CDR0000800108__2094"><li class="half_rhythm"><div>Compared with adults, children showed higher prevalence of hereditary (80.4% vs. 52.6%), extra-adrenal (66.3% vs. 35.1%), multifocal (32.6% vs. 13.5%), metastatic (49.5% vs. 29.1%), and recurrent (29.5% vs. 14.2%) pheochromocytoma or paraganglioma.</div></li><li class="half_rhythm"><div>Tumors caused by cluster 1 variants, which are associated with the absence of epinephrine production, were more prevalent among children than adults (76% vs. 39%; <i>P</i> < .0001). This difference paralleled a higher prevalence of noradrenergic tumors in children, characterized by a relative lack of increased plasma metanephrine (93.2% vs. 57.3%). </div></li></ul></div></li><li class="half_rhythm"><div class="half_rhythm">The U.S. National Institutes of Health reported the clinical characteristics and outcomes of 64 pediatric patients who had pheochromocytoma or paraganglioma with <i>SDHB</i> germline pathogenic variants. There were 38 males and 26 females diagnosed at a median age of 13 years.[<a class="bibr" href="#CDR0000800108_rl_873_7" rid="CDR0000800108_rl_873_7">7</a>] <ul id="CDR0000800108__2385"><li class="half_rhythm"><div>Most patients displayed norepinephrine hypersecretion, and 73% of patients initially presented with a solitary tumor.</div></li><li class="half_rhythm"><div>Metastasis developed in 70% of patients at a median age of 16 years. Most patients were diagnosed with metastasis in the first 2 years after the initial diagnosis and in years 12 to 18 postdiagnosis.</div></li><li class="half_rhythm"><div>The presence of metastasis at the time of diagnosis had a strong negative impact on survival in males but not in females. </div></li><li class="half_rhythm"><div>The estimated 5-year survival rate was 100%; the 10-year survival rate was 97.14%; the 20-year survival rate was 77.71%.</div></li><li class="half_rhythm"><div>These tumors are relatively slow growing, which explains the late deaths and the need for prolonged follow-up.</div></li><li class="half_rhythm"><div>The authors recommended that the initial diagnostic evaluation of <i>SDHB</i> variant carriers should begin at age 5 to 6 years, with initial work-up focusing on the abdominal region. Thorough monitoring of patients is crucial in the first 2 years after diagnosis, and more frequent follow-up evaluations are needed in years 10 to 20 postdiagnosis because of the increased risk of metastasis.</div></li></ul>
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</div></li></ol><p id="CDR0000800108__877">Immunohistochemical <i>SDHB</i> staining may help triage genetic testing. Tumors of patients with <i>SDHB</i>, <i>SDHC</i>, and <i>SDHD</i> variants have absent or weak staining, while sporadic tumors and those associated with other constitutional syndromes have positive staining.[<a class="bibr" href="#CDR0000800108_rl_873_8" rid="CDR0000800108_rl_873_8">8</a>,<a class="bibr" href="#CDR0000800108_rl_873_9" rid="CDR0000800108_rl_873_9">9</a>] Therefore, immunohistochemical <i>SDHB</i> staining can help identify potential carriers of <i>SDH</i> variants early, obviating the need for extensive and costly testing of other genes. Early identification of young patients with <i>SDHB</i> variants using radiographic, serological, and immunohistochemical markers could potentially decrease mortality and identify other family members who carry a germline <i>SDHB</i> pathogenic variant.</p><p id="CDR0000800108__2112">Given the higher prevalence of germline alterations in children and adolescents with pheochromocytoma and paraganglioma, genetic counseling and testing should be considered in this younger population.</p><div id="CDR0000800108__871"><h3>Clinical Presentation</h3><p id="CDR0000800108__872">Patients with pheochromocytoma and sympathetic extra-adrenal paraganglioma usually present with the following symptoms of excess catecholamine production:</p><ul id="CDR0000800108__1445"><li class="half_rhythm"><div>Hypertension.</div></li><li class="half_rhythm"><div>Headache.</div></li><li class="half_rhythm"><div>Perspiration.</div></li><li class="half_rhythm"><div>Palpitations.</div></li><li class="half_rhythm"><div>Tremor.</div></li><li class="half_rhythm"><div>Facial pallor. </div></li></ul><p id="CDR0000800108__2397">In one study, 2,291 adult patients were evaluated for the diagnosis of pheochromocytoma and paraganglioma. Patients were tested because of initial signs or symptoms, detection of an incidental mass on imaging or during routine surveillance because of a previous history of pheochromocytoma or paraganglioma, or a hereditary risk associated with a variant of a tumor susceptibility gene. The study used a 7-point clinical scoring system that included pallor, hyperhidrosis, palpitations, tremor, nausea, body mass index of less than 25 kg/m<sup>2</sup>, and heart rate of 85 beats per minute or higher to identify patients at risk of having pheochromocytoma or paraganglioma. A score of 3 or higher was associated with a 5.8-fold higher likelihood of being diagnosed with a paraganglioma or a pheochromocytoma, compared with patients who had a lower score.[<a class="bibr" href="#CDR0000800108_rl_873_10" rid="CDR0000800108_rl_873_10">10</a>] This scoring system may not be applicable to pediatric patients.</p><p id="CDR0000800108__1446">Symptoms of pheochromocytoma and paraganglioma can be paroxysmal, although sustained hypertension between paroxysmal episodes occurs in more than one-half of patients. These symptoms can also be induced by exertion, trauma, induction of anesthesia, resection of the tumor, consumption of foods high in tyramine (e.g., red wine, chocolate, cheese), or urination (in cases of primary tumor of the bladder).[<a class="bibr" href="#CDR0000800108_rl_873_11" rid="CDR0000800108_rl_873_11">11</a>]</p><p id="CDR0000800108__1305">Parasympathetic extra-adrenal paragangliomas do not secrete catecholamines and usually present as a neck mass with symptoms related to compression, but also may be asymptomatic and diagnosed incidentally.[<a class="bibr" href="#CDR0000800108_rl_873_11" rid="CDR0000800108_rl_873_11">11</a>] Epinephrine production is also associated with cluster genotype. Cluster 1 tumors are characterized by absence of epinephrine production (noradrenergic phenotype), whereas cluster 2 tumors produce epinephrine (adrenergic phenotype).[<a class="bibr" href="#CDR0000800108_rl_873_6" rid="CDR0000800108_rl_873_6">6</a>]</p><p id="CDR0000800108__1306">The pediatric and adolescent patient appears to present with symptoms similar to those of the adult patient, although with more frequent sustained hypertension.[<a class="bibr" href="#CDR0000800108_rl_873_12" rid="CDR0000800108_rl_873_12">12</a>] The clinical behavior of paraganglioma and pheochromocytoma appears to be more aggressive in children and adolescents than in adults, and metastatic rates of up to 50% have been reported.[<a class="bibr" href="#CDR0000800108_rl_873_1" rid="CDR0000800108_rl_873_1">1</a>,<a class="bibr" href="#CDR0000800108_rl_873_12" rid="CDR0000800108_rl_873_12">12</a>,<a class="bibr" href="#CDR0000800108_rl_873_13" rid="CDR0000800108_rl_873_13">13</a>] As previously discussed, children and adolescents with pheochromocytoma and paraganglioma have a higher prevalence of hereditary, extra-adrenal, multifocal, metastatic, and recurrent pheochromocytomas and paragangliomas. They also have a higher prevalence of cluster 1 variants, which is paralleled by a higher prevalence of noradrenergic tumors than in adults.[<a class="bibr" href="#CDR0000800108_rl_873_6" rid="CDR0000800108_rl_873_6">6</a>]</p></div><div id="CDR0000800108__878"><h3>Diagnostic Evaluation</h3><p id="CDR0000800108__879">The diagnosis of paraganglioma and pheochromocytoma relies on the biochemical documentation of excess catecholamine secretion coupled with imaging studies for localization and staging:</p><ul id="CDR0000800108__1447"><li class="half_rhythm"><div class="half_rhythm"><b>Biochemical testing:</b> Measurement of plasma-free fractionated metanephrines (metanephrine and normetanephrine) is usually the diagnostic tool of choice when a secreting paraganglioma or pheochromocytoma is suspected. A 24-hour urine collection for catecholamines (epinephrine, norepinephrine, and dopamine) and fractionated metanephrines can also be performed for confirmation.[<a class="bibr" href="#CDR0000800108_rl_873_14" rid="CDR0000800108_rl_873_14">14</a>,<a class="bibr" href="#CDR0000800108_rl_873_15" rid="CDR0000800108_rl_873_15">15</a>]</div><div class="half_rhythm">Catecholamine metabolic and secretory profiles are impacted by hereditary background. Both hereditary and sporadic paraganglioma and pheochromocytoma differ markedly in tumor contents of catecholamines and corresponding plasma and urinary hormonal profiles. About 50% of secreting tumors produce and contain a mixture of norepinephrine and epinephrine, while most of the rest produce norepinephrine almost exclusively, with occasional rare tumors producing mainly dopamine. Patients with epinephrine-producing tumors are diagnosed later (median age, 50 years) than those with tumors lacking appreciable epinephrine production (median age, 40 years). Patients with multiple endocrine neoplasia type 2 (MEN2) and neurofibromatosis type 1 (NF1) syndromes, all with epinephrine-producing tumors, are typically diagnosed at a later age (median age, 40 years) than are patients with tumors that lack appreciable epinephrine production secondary to variants of <i>VHL</i> and <i>SDH</i> (median age, 30 years). These variations in ages at diagnosis associated with different tumor catecholamine phenotypes and locations suggest origins of paraganglioma and pheochromocytoma for different progenitor cells with variable susceptibility to disease-causing variants.[<a class="bibr" href="#CDR0000800108_rl_873_16" rid="CDR0000800108_rl_873_16">16</a>,<a class="bibr" href="#CDR0000800108_rl_873_17" rid="CDR0000800108_rl_873_17">17</a>]</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Imaging:</b> Imaging modalities used for the localization of paraganglioma and pheochromocytoma include the following:<dl id="CDR0000800108__1312" class="temp-labeled-list"><dl class="bkr_refwrap"><dt>-</dt><dd><p class="no_top_margin">Computed tomography (CT).</p></dd></dl><dl class="bkr_refwrap"><dt>-</dt><dd><p class="no_top_margin">Magnetic resonance imaging (MRI).</p></dd></dl><dl class="bkr_refwrap"><dt>-</dt><dd><p class="no_top_margin">Iodine I 123 or iodine I 131-labeled metaiodobenzylguanidine (123/131I-MIBG) scintigraphy, fluorine F 18-fluorodihydroxyphenylalanine (18F-FDOPA) positron emission tomography (PET)-CT, gallium Ga 68-DOTATATE (68Ga-DOTATATE) PET-CT, and fluorine F 18-6-fluorodopamine (18F-6-FDA) PET.[<a class="bibr" href="#CDR0000800108_rl_873_18" rid="CDR0000800108_rl_873_18">18</a>,<a class="bibr" href="#CDR0000800108_rl_873_19" rid="CDR0000800108_rl_873_19">19</a>]</p></dd></dl></dl></div><div class="half_rhythm">For tumor localization, 18F-6-FDA PET and 123/131I-MIBG scintigraphy perform equally well in patients with nonmetastatic paraganglioma and pheochromocytoma. However, metastases are better detected by 18F-6-FDA PET than by 123/131I-MIBG.[<a class="bibr" href="#CDR0000800108_rl_873_20" rid="CDR0000800108_rl_873_20">20</a>,<a class="bibr" href="#CDR0000800108_rl_873_21" rid="CDR0000800108_rl_873_21">21</a>] For patients with cluster 1A tumors, the most sensitive modality is 68Ga-DOTATATE PET-CT. For patients with cluster 1B tumors, 18F-FDOPA PET is preferred. Cluster 2 tumors are usually identified using CT or MRI, and the most sensitive functional imaging method is 18F-FDOPA PET.[<a class="bibr" href="#CDR0000800108_rl_873_22" rid="CDR0000800108_rl_873_22">22</a>] Other functional imaging alternatives include indium In 111-octreotide scintigraphy and fluorine F 18-fludeoxyglucose (18F-FDG) PET, both of which can be coupled with CT imaging for improved anatomic detail.</div><div class="half_rhythm">A single-institution retrospective evaluation of consecutive pediatric patients with pheochromocytoma and paraganglioma (aged, ≤20 years) compared functional imaging with 131I-MIBG, 18F-FDG PET-CT, and 68Ga-DOTATATE PET-CT.[<a class="bibr" href="#CDR0000800108_rl_873_23" rid="CDR0000800108_rl_873_23">23</a>] In a cohort of 32 patients (16 males; age at diagnosis, 16.4 ± 2.68 years), lesion-wise sensitivity of 68Ga-DOTATATE PET-CT (95%) was higher than that of both 18F-FDG PET-CT (80%, <i>P</i> = .027) and 131I-MIBG (65%, <i>P</i> = .0004) for overall lesions. Lesion-wide sensitivity of 68Ga-DOTATATE PET-CT was also higher than that of 18F-FDG PET-CT (100% vs. 67%, <i>P</i> = .017) for primary paraganglioma and that of 131I-MIBG (93% vs. 42%, <i>P</i> = .0001) for metastases.
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</div></li></ul><p id="CDR0000800108__2422">An international panel of experts has published consensus guidelines on the initial screening and follow-up of adults and children who are asymptomatic carriers of a germline pathogenic variant in one of the <i>SDH</i> genes.[<a class="bibr" href="#CDR0000800108_rl_873_24" rid="CDR0000800108_rl_873_24">24</a>]</p></div><div id="CDR0000800108_rl_873"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000800108_rl_873_1">King KS, Prodanov T, Kantorovich V, et al.: Metastatic pheochromocytoma/paraganglioma related to primary tumor development in childhood or adolescence: significant link to SDHB mutations. J Clin Oncol 29 (31): 4137-42, 2011. 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[<a href="https://pubmed.ncbi.nlm.nih.gov/20236688" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20236688</span></a>]</div></li><li><div class="bk_ref" id="CDR0000800108_rl_873_9">van Nederveen FH, Gaal J, Favier J, et al.: An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: a retrospective and prospective analysis. Lancet Oncol 10 (8): 764-71, 2009. [<a href="/pmc/articles/PMC4718191/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4718191</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19576851" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19576851</span></a>]</div></li><li><div class="bk_ref" id="CDR0000800108_rl_873_10">Geroula A, Deutschbein T, Langton K, et al.: Pheochromocytoma and paraganglioma: clinical feature-based disease probability in relation to catecholamine biochemistry and reason for disease suspicion. Eur J Endocrinol 181 (4): 409-420, 2019. [<a href="https://pubmed.ncbi.nlm.nih.gov/31370000" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31370000</span></a>]</div></li><li><div class="bk_ref" id="CDR0000800108_rl_873_11">Lenders JW, Eisenhofer G, Mannelli M, et al.: Phaeochromocytoma. Lancet 366 (9486): 665-75, 2005 Aug 20-26. [<a href="https://pubmed.ncbi.nlm.nih.gov/16112304" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16112304</span></a>]</div></li><li><div class="bk_ref" id="CDR0000800108_rl_873_12">Pham TH, Moir C, Thompson GB, et al.: Pheochromocytoma and paraganglioma in children: a review of medical and surgical management at a tertiary care center. Pediatrics 118 (3): 1109-17, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16951005" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16951005</span></a>]</div></li><li><div class="bk_ref" id="CDR0000800108_rl_873_13">Waguespack SG, Rich T, Grubbs E, et al.: A current review of the etiology, diagnosis, and treatment of pediatric pheochromocytoma and paraganglioma. J Clin Endocrinol Metab 95 (5): 2023-37, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20215394" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20215394</span></a>]</div></li><li><div class="bk_ref" id="CDR0000800108_rl_873_14">Lenders JW, Pacak K, Walther MM, et al.: Biochemical diagnosis of pheochromocytoma: which test is best? JAMA 287 (11): 1427-34, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/11903030" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11903030</span></a>]</div></li><li><div class="bk_ref" id="CDR0000800108_rl_873_15">Sarathi V, Pandit R, Patil VK, et al.: Performance of plasma fractionated free metanephrines by enzyme immunoassay in the diagnosis of pheochromocytoma and paraganglioma in children. Endocr Pract 18 (5): 694-9, 2012 Sep-Oct. [<a href="https://pubmed.ncbi.nlm.nih.gov/22982790" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22982790</span></a>]</div></li><li><div class="bk_ref" id="CDR0000800108_rl_873_16">Eisenhofer G, Pacak K, Huynh TT, et al.: Catecholamine metabolomic and secretory phenotypes in phaeochromocytoma. Endocr Relat Cancer 18 (1): 97-111, 2011. [<a href="/pmc/articles/PMC3671349/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3671349</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21051559" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21051559</span></a>]</div></li><li><div class="bk_ref" id="CDR0000800108_rl_873_17">Eisenhofer G, Timmers HJ, Lenders JW, et al.: Age at diagnosis of pheochromocytoma differs according to catecholamine phenotype and tumor location. J Clin Endocrinol Metab 96 (2): 375-84, 2011. [<a href="/pmc/articles/PMC3048320/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3048320</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21147885" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21147885</span></a>]</div></li><li><div class="bk_ref" id="CDR0000800108_rl_873_18">Taïeb D, Neumann H, Rubello D, et al.: Modern nuclear imaging for paragangliomas: beyond SPECT. J Nucl Med 53 (2): 264-74, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/22302963" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22302963</span></a>]</div></li><li><div class="bk_ref" id="CDR0000800108_rl_873_19">Janssen I, Blanchet EM, Adams K, et al.: Superiority of [68Ga]-DOTATATE PET/CT to Other Functional Imaging Modalities in the Localization of SDHB-Associated Metastatic Pheochromocytoma and Paraganglioma. Clin Cancer Res 21 (17): 3888-95, 2015. [<a href="/pmc/articles/PMC4558308/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4558308</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25873086" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25873086</span></a>]</div></li><li><div class="bk_ref" id="CDR0000800108_rl_873_20">Timmers HJ, Chen CC, Carrasquillo JA, et al.: Comparison of 18F-fluoro-L-DOPA, 18F-fluoro-deoxyglucose, and 18F-fluorodopamine PET and 123I-MIBG scintigraphy in the localization of pheochromocytoma and paraganglioma. J Clin Endocrinol Metab 94 (12): 4757-67, 2009. [<a href="/pmc/articles/PMC2795662/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2795662</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19864450" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19864450</span></a>]</div></li><li><div class="bk_ref" id="CDR0000800108_rl_873_21">Sait S, Pandit-Taskar N, Modak S: Failure of MIBG scan to detect metastases in SDHB-mutated pediatric metastatic pheochromocytoma. Pediatr Blood Cancer 64 (11): , 2017. [<a href="https://pubmed.ncbi.nlm.nih.gov/28409892" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28409892</span></a>]</div></li><li><div class="bk_ref" id="CDR0000800108_rl_873_22">Nölting S, Bechmann N, Taieb D, et al.: Personalized Management of Pheochromocytoma and Paraganglioma. Endocr Rev 43 (2): 199-239, 2022. [<a href="/pmc/articles/PMC8905338/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC8905338</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/34147030" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 34147030</span></a>]</div></li><li><div class="bk_ref" id="CDR0000800108_rl_873_23">Jaiswal SK, Sarathi V, Malhotra G, et al.: The utility of 68Ga-DOTATATE PET/CT in localizing primary/metastatic pheochromocytoma and paraganglioma in children and adolescents - a single-center experience. J Pediatr Endocrinol Metab 34 (1): 109-119, 2021. [<a href="https://pubmed.ncbi.nlm.nih.gov/33180042" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33180042</span></a>]</div></li><li><div class="bk_ref" id="CDR0000800108_rl_873_24">Amar L, Pacak K, Steichen O, et al.: International consensus on initial screening and follow-up of asymptomatic SDHx mutation carriers. Nat Rev Endocrinol 17 (7): 435-444, 2021. [<a href="/pmc/articles/PMC8205850/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC8205850</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/34021277" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 34021277</span></a>]</div></li></ol></div></div><div id="CDR0000800108__1864"><h2 id="_CDR0000800108__1864_">Special Considerations for the Treatment of Children With Cancer</h2><p id="CDR0000800108__1864_md_3">Cancer in children and adolescents is rare, although the overall incidence has slowly increased since 1975.[<a class="bibr" href="#CDR0000800108_rl_1864_1" rid="CDR0000800108_rl_1864_1">1</a>] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills
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of the following pediatric specialists and others to ensure that children receive treatment, supportive care, and rehabilitation
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to achieve optimal survival and quality of life:</p><ul id="CDR0000800108__1864_md_4"><li class="half_rhythm"><div>Primary care physicians.</div></li><li class="half_rhythm"><div>Pediatric surgeons.</div></li><li class="half_rhythm"><div>Pathologists.</div></li><li class="half_rhythm"><div>Pediatric radiation
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oncologists.</div></li><li class="half_rhythm"><div>Pediatric medical oncologists and hematologists.</div></li><li class="half_rhythm"><div>Ophthalmologists.</div></li><li class="half_rhythm"><div> Rehabilitation
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specialists.</div></li><li class="half_rhythm"><div>Pediatric oncology nurses.</div></li><li class="half_rhythm"><div>Social workers.</div></li><li class="half_rhythm"><div>Child-life professionals.</div></li><li class="half_rhythm"><div>Psychologists.</div></li><li class="half_rhythm"><div>Nutritionists.</div></li></ul><p id="CDR0000800108__1864_md_5">For specific information about supportive care for children and adolescents with cancer, see the summaries on <a href="https://www.cancer.gov/publications/pdq/information-summaries/supportive-care" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Supportive and Palliative Care</a>.</p><p id="CDR0000800108__1864_md_6">The American Academy of Pediatrics has outlined guidelines for
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pediatric cancer centers and their role in the treatment of children and adolescents
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with cancer.[<a class="bibr" href="#CDR0000800108_rl_1864_2" rid="CDR0000800108_rl_1864_2">2</a>] At
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these centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity
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to participate is offered to most patients and their families. Clinical
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trials for children and adolescents diagnosed with cancer are generally
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designed to compare potentially better therapy with current standard therapy. Other types of clinical trials test novel therapies when there is no standard therapy for a cancer diagnosis. Most of the progress in identifying curative
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therapies for childhood cancers has been achieved through clinical trials.
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Information about ongoing clinical trials is available from the <a href="https://www.cancer.gov/research/participate/clinical-trials" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI website</a>.</p><p id="CDR0000800108__1864_md_7">Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2020, childhood cancer mortality decreased by more than 50%.[<a class="bibr" href="#CDR0000800108_rl_1864_3" rid="CDR0000800108_rl_1864_3">3</a>-<a class="bibr" href="#CDR0000800108_rl_1864_5" rid="CDR0000800108_rl_1864_5">5</a>] Childhood and adolescent cancer survivors require close monitoring because side effects of cancer therapy may persist or develop months or years after treatment. For information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors, see <a href="/books/n/pdqcis/CDR0000343584/?report=reader">Late Effects of Treatment for Childhood Cancer</a>.</p><p id="CDR0000800108__1864_md_8">Childhood cancer is a rare disease, with about 15,000 cases diagnosed annually in the United States in individuals younger than 20 years.[<a class="bibr" href="#CDR0000800108_rl_1864_6" rid="CDR0000800108_rl_1864_6">6</a>] The U.S. <a href="https://www.congress.gov/107/plaws/publ280/PLAW-107publ280.pdf" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Rare Diseases Act of 2002</a> defines a rare disease as one that affects populations smaller than 200,000 people in the United States. Therefore, all pediatric cancers are considered rare.</p><p id="CDR0000800108__1864_md_9">The designation of a rare tumor is not uniform among pediatric and adult groups. In adults, rare cancers are defined as those with an annual incidence of fewer than six cases per 100,000 people. They account for up to 24% of all cancers diagnosed in the European Union and about 20% of all cancers diagnosed in the United States.[<a class="bibr" href="#CDR0000800108_rl_1864_7" rid="CDR0000800108_rl_1864_7">7</a>,<a class="bibr" href="#CDR0000800108_rl_1864_8" rid="CDR0000800108_rl_1864_8">8</a>] In children and adolescents, the designation of a rare tumor is not uniform among international groups, as follows:</p><ul id="CDR0000800108__1864_md_10"><li class="half_rhythm"><div class="half_rhythm">A consensus effort between the European Union Joint Action on Rare Cancers and the European Cooperative Study Group for Rare Pediatric Cancers estimated that 11% of all cancers in patients younger than 20 years could be categorized as very rare. This consensus group defined very rare cancers as those with annual incidences of fewer than two cases per 1 million people. However, three additional histologies (thyroid carcinoma, melanoma, and testicular cancer) with incidences of more than two cases per 1 million people were also included in the very rare group due to a lack of knowledge and expertise in the management of these tumors.[<a class="bibr" href="#CDR0000800108_rl_1864_9" rid="CDR0000800108_rl_1864_9">9</a>]</div></li><li class="half_rhythm"><div class="half_rhythm">The Children's Oncology Group defines rare pediatric cancers as those listed in the International Classification of Childhood Cancer subgroup XI, which includes thyroid cancers, melanomas and nonmelanoma skin cancers, and multiple types of carcinomas (e.g., adrenocortical carcinomas, nasopharyngeal carcinomas, and most adult-type carcinomas such as breast cancers and colorectal cancers).[<a class="bibr" href="#CDR0000800108_rl_1864_10" rid="CDR0000800108_rl_1864_10">10</a>] These diagnoses account for about 5% of the cancers diagnosed in children aged 0 to 14 years and about 27% of the cancers diagnosed in adolescents aged 15 to 19 years.[<a class="bibr" href="#CDR0000800108_rl_1864_4" rid="CDR0000800108_rl_1864_4">4</a>]</div><div class="half_rhythm"> Most cancers in subgroup XI are either melanomas or thyroid cancers, with other cancer types accounting for only 2% of the cancers diagnosed in children aged 0 to 14 years and 9.3% of the cancers diagnosed in adolescents aged 15 to 19 years.</div></li></ul><p id="CDR0000800108__1864_md_12">These rare cancers are extremely challenging to study because of the relatively few patients with any individual diagnosis, the predominance of rare cancers in the adolescent population, and the small number of clinical trials for adolescents with rare cancers.</p><p id="CDR0000800108__1837">Information about these tumors may also be found in sources relevant to
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adults with cancer, such as <a href="/books/n/pdqcis/CDR0000681246/?report=reader">Pheochromocytoma and Paraganglioma Treatment</a>.</p><div id="CDR0000800108_rl_1864"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000800108_rl_1864_1">Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010. [<a href="/pmc/articles/PMC2881732/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2881732</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20404250" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20404250</span></a>]</div></li><li><div class="bk_ref" id="CDR0000800108_rl_1864_2">American Academy of Pediatrics: Standards for pediatric cancer centers. Pediatrics 134 (2): 410-4, 2014. <a href="https://pediatrics.aappublications.org/content/134/2/410" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">Also available online</a>. Last accessed August 23, 2024.</div></li><li><div class="bk_ref" id="CDR0000800108_rl_1864_3">Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [<a href="/pmc/articles/PMC4136455/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4136455</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24853691" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24853691</span></a>]</div></li><li><div class="bk_ref" id="CDR0000800108_rl_1864_4">National Cancer Institute: NCCR*Explorer: An interactive website for NCCR cancer statistics. Bethesda, MD: National Cancer Institute. <a href="https://NCCRExplorer.ccdi.cancer.gov/" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">Available online</a>. Last accessed August 23, 2024.</div></li><li><div class="bk_ref" id="CDR0000800108_rl_1864_5">Surveillance Research Program, National Cancer Institute: SEER*Explorer: An interactive website for SEER cancer statistics. Bethesda, MD: National Cancer Institute. <a href="https://seer.cancer.gov/statistics-network/explorer/" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">Available online</a>. Last accessed December 30, 2024.</div></li><li><div class="bk_ref" id="CDR0000800108_rl_1864_6">Ward E, DeSantis C, Robbins A, et al.: Childhood and adolescent cancer statistics, 2014. CA Cancer J Clin 64 (2): 83-103, 2014 Mar-Apr. [<a href="https://pubmed.ncbi.nlm.nih.gov/24488779" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24488779</span></a>]</div></li><li><div class="bk_ref" id="CDR0000800108_rl_1864_7">Gatta G, Capocaccia R, Botta L, et al.: Burden and centralised treatment in Europe of rare tumours: results of RARECAREnet-a population-based study. Lancet Oncol 18 (8): 1022-1039, 2017. [<a href="https://pubmed.ncbi.nlm.nih.gov/28687376" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28687376</span></a>]</div></li><li><div class="bk_ref" id="CDR0000800108_rl_1864_8">DeSantis CE, Kramer JL, Jemal A: The burden of rare cancers in the United States. CA Cancer J Clin 67 (4): 261-272, 2017. [<a href="https://pubmed.ncbi.nlm.nih.gov/28542893" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28542893</span></a>]</div></li><li><div class="bk_ref" id="CDR0000800108_rl_1864_9">Ferrari A, Brecht IB, Gatta G, et al.: Defining and listing very rare cancers of paediatric age: consensus of the Joint Action on Rare Cancers in cooperation with the European Cooperative Study Group for Pediatric Rare Tumors. Eur J Cancer 110: 120-126, 2019. [<a href="https://pubmed.ncbi.nlm.nih.gov/30785015" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30785015</span></a>]</div></li><li><div class="bk_ref" id="CDR0000800108_rl_1864_10">Pappo AS, Krailo M, Chen Z, et al.: Infrequent tumor initiative of the Children's Oncology Group: initial lessons learned and their impact on future plans. J Clin Oncol 28 (33): 5011-6, 2010. [<a href="/pmc/articles/PMC3020699/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3020699</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20956621" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20956621</span></a>]</div></li></ol></div></div><div id="CDR0000800108__885"><h2 id="_CDR0000800108__885_">Treatment of Childhood Pheochromocytoma and Paraganglioma</h2><p id="CDR0000800108__2271">Treatment options for childhood paraganglioma and pheochromocytoma include the following:</p><ol id="CDR0000800108__2272"><li class="half_rhythm"><div>Surgery.</div></li><li class="half_rhythm"><div>Chemotherapy for patients with metastatic disease.</div></li><li class="half_rhythm"><div>High-dose iodine I 131-labeled metaiodobenzylguanidine (131I-MIBG).</div></li><li class="half_rhythm"><div>Lutetium Lu 177-DOTATATE and Yttrium Y 90-DOTATOC.[<a class="bibr" href="#CDR0000800108_rl_885_1" rid="CDR0000800108_rl_885_1">1</a>]</div></li><li class="half_rhythm"><div>Tyrosine kinase inhibitor therapy (sunitinib and cabozantinib).[<a class="bibr" href="#CDR0000800108_rl_885_1" rid="CDR0000800108_rl_885_1">1</a>]</div></li><li class="half_rhythm"><div>mTOR inhibitors.[<a class="bibr" href="#CDR0000800108_rl_885_1" rid="CDR0000800108_rl_885_1">1</a>]</div></li><li class="half_rhythm"><div>Immunotherapy.[<a class="bibr" href="#CDR0000800108_rl_885_1" rid="CDR0000800108_rl_885_1">1</a>]</div></li></ol><p id="CDR0000800108__886">Treatment of paraganglioma and pheochromocytoma is surgical. For secreting tumors, alpha- and beta-adrenergic blockade must be optimized before surgery. A single-institution study reviewed the experience of laparoscopic partial adrenalectomy for bilateral pheochromocytoma in patients with von Hippel-Lindau disease.[<a class="bibr" href="#CDR0000800108_rl_885_2" rid="CDR0000800108_rl_885_2">2</a>] In eight patients, all 16 adrenalectomies were performed laparoscopically. Fourteen of the procedures were partial adrenalectomies, and two patients required a contralateral total adrenalectomy because of tumor size and diffuse multinodularity. Two patients had new ipsilateral tumors identified after a median follow-up of 5 years (range, 4–6 years), with one patient who underwent repeat partial adrenalectomy. There were no deaths during the study period.</p><p id="CDR0000800108__1314">For patients with metastatic disease, responses have been documented to some chemotherapeutic regimens such as gemcitabine and docetaxel or different combinations of vincristine, cyclophosphamide, doxorubicin, and dacarbazine.[<a class="bibr" href="#CDR0000800108_rl_885_3" rid="CDR0000800108_rl_885_3">3</a>-<a class="bibr" href="#CDR0000800108_rl_885_5" rid="CDR0000800108_rl_885_5">5</a>] Chemotherapy may help alleviate symptoms and facilitate surgery, although its impact on overall survival is less clear. </p><p id="CDR0000800108__1315">Responses have also been obtained with high-dose 131I-MIBG and sunitinib.[<a class="bibr" href="#CDR0000800108_rl_885_6" rid="CDR0000800108_rl_885_6">6</a>,<a class="bibr" href="#CDR0000800108_rl_885_7" rid="CDR0000800108_rl_885_7">7</a>]</p><p id="CDR0000800108__2423">Specific consensus guidelines for the diagnosis and management of pheochromocytoma and paraganglioma in patients with germline <i>SDHB</i> and <i>SDHD</i> pathogenic variants have been published.[<a class="bibr" href="#CDR0000800108_rl_885_8" rid="CDR0000800108_rl_885_8">8</a>,<a class="bibr" href="#CDR0000800108_rl_885_9" rid="CDR0000800108_rl_885_9">9</a>]</p><div id="CDR0000800108_rl_885"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000800108_rl_885_1">Granberg D, Juhlin CC, Falhammar H: Metastatic Pheochromocytomas and Abdominal Paragangliomas. J Clin Endocrinol Metab 106 (5): e1937-e1952, 2021. [<a href="/pmc/articles/PMC8063253/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC8063253</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/33462603" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33462603</span></a>]</div></li><li><div class="bk_ref" id="CDR0000800108_rl_885_2">Rubalcava NS, Overman RE, Kartal TT, et al.: Laparoscopic adrenal-sparing approach for children with bilateral pheochromocytoma in Von Hippel-Lindau disease. J Pediatr Surg 57 (3): 414-417, 2022. [<a href="https://pubmed.ncbi.nlm.nih.gov/34016427" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 34016427</span></a>]</div></li><li><div class="bk_ref" id="CDR0000800108_rl_885_3">Mora J, Cruz O, Parareda A, et al.: Treatment of disseminated paraganglioma with gemcitabine and docetaxel. Pediatr Blood Cancer 53 (4): 663-5, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19405123" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19405123</span></a>]</div></li><li><div class="bk_ref" id="CDR0000800108_rl_885_4">Huang H, Abraham J, Hung E, et al.: Treatment of malignant pheochromocytoma/paraganglioma with cyclophosphamide, vincristine, and dacarbazine: recommendation from a 22-year follow-up of 18 patients. Cancer 113 (8): 2020-8, 2008. [<a href="/pmc/articles/PMC9094399/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC9094399</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18780317" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18780317</span></a>]</div></li><li><div class="bk_ref" id="CDR0000800108_rl_885_5">Patel SR, Winchester DJ, Benjamin RS: A 15-year experience with chemotherapy of patients with paraganglioma. Cancer 76 (8): 1476-80, 1995. [<a href="https://pubmed.ncbi.nlm.nih.gov/8620426" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8620426</span></a>]</div></li><li><div class="bk_ref" id="CDR0000800108_rl_885_6">Gonias S, Goldsby R, Matthay KK, et al.: Phase II study of high-dose [131I]metaiodobenzylguanidine therapy for patients with metastatic pheochromocytoma and paraganglioma. J Clin Oncol 27 (25): 4162-8, 2009. [<a href="/pmc/articles/PMC2734428/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2734428</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19636009" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19636009</span></a>]</div></li><li><div class="bk_ref" id="CDR0000800108_rl_885_7">Joshua AM, Ezzat S, Asa SL, et al.: Rationale and evidence for sunitinib in the treatment of malignant paraganglioma/pheochromocytoma. J Clin Endocrinol Metab 94 (1): 5-9, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19001511" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19001511</span></a>]</div></li><li><div class="bk_ref" id="CDR0000800108_rl_885_8">Taïeb D, Wanna GB, Ahmad M, et al.: Clinical consensus guideline on the management of phaeochromocytoma and paraganglioma in patients harbouring germline SDHD pathogenic variants. Lancet Diabetes Endocrinol 11 (5): 345-361, 2023. [<a href="/pmc/articles/PMC10182476/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC10182476</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/37011647" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 37011647</span></a>]</div></li><li><div class="bk_ref" id="CDR0000800108_rl_885_9">Taïeb D, Nölting S, Perrier ND, et al.: Management of phaeochromocytoma and paraganglioma in patients with germline SDHB pathogenic variants: an international expert Consensus statement. Nat Rev Endocrinol 20 (3): 168-184, 2024. [<a href="https://pubmed.ncbi.nlm.nih.gov/38097671" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 38097671</span></a>]</div></li></ol></div></div><div id="CDR0000800108__1990"><h2 id="_CDR0000800108__1990_">Treatment Options Under Clinical Evaluation for Childhood Pheochromocytoma and Paraganglioma</h2><p id="CDR0000800108__1991">Information about National Cancer Institute (NCI)–supported clinical trials can be found on the <a href="https://www.cancer.gov/research/participate/clinical-trials-search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI website</a>. For information about clinical trials sponsored by other organizations, see the <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov website</a>.</p><p id="CDR0000800108__1992">The following are examples of national and/or institutional clinical trials that are currently being conducted:</p><ul id="CDR0000800108__1993"><li class="half_rhythm"><div><b><a href="https://www.cancer.gov/clinicaltrials/NCT04924075" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCT04924075</a></b> (Belzutifan/MK-6482 for the Treatment of Advanced Pheochromocytoma and Paraganglioma or Pancreatic Neuroendocrine Tumor)<b>:</b> This study will evaluate the efficacy and safety of belzutifan monotherapy in participants with advanced pheochromocytoma or paraganglioma or pancreatic neuroendocrine tumor. The primary goal is to evaluate the objective response rate of belzutifan per Response Evaluation Criteria in Solid Tumors Version 1.1 by blinded independent central review.</div></li><li class="half_rhythm"><div><b><a href="https://www.cancer.gov/clinicaltrials/NCT04394858" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCT04394858</a></b> (Testing the Addition of an Anticancer Drug, Olaparib, to the Usual Chemotherapy [Temozolomide] for Advanced Neuroendocrine Cancer)<b>:</b> This phase II trial will study the effectiveness of the addition of olaparib to temozolomide (the usual treatment) in treating patients aged 18 years and older with metastatic or unresectable pheochromocytomas or paragangliomas.</div></li></ul></div><div id="CDR0000800108__2381"><h2 id="_CDR0000800108__2381_">Latest Updates to This Summary (09/09/2024)</h2><p id="CDR0000800108__2382">The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.</p><p id="CDR0000800108__2421">This summary was comprehensively reviewed.</p><p id="CDR0000800108__disclaimerHP_3">This summary is written and maintained by the <a href="https://www.cancer.gov/publications/pdq/editorial-boards/pediatric-treatment" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PDQ Pediatric Treatment Editorial Board</a>, which is
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editorially independent of NCI. The summary reflects an independent review of
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the literature and does not represent a policy statement of NCI or NIH. More
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information about summary policies and the role of the PDQ Editorial Boards in
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maintaining the PDQ summaries can be found on the <a href="#CDR0000800108__AboutThis_1">About This PDQ Summary</a> and <a href="https://www.cancer.gov/publications/pdq" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PDQ® Cancer Information for Health Professionals</a> pages.
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</p></div><div id="CDR0000800108__AboutThis_1"><h2 id="_CDR0000800108__AboutThis_1_">About This PDQ Summary</h2><div id="CDR0000800108__AboutThis_2"><h3>Purpose of This Summary</h3><p id="CDR0000800108__AboutThis_3">This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of pediatric pheochromocytoma and paraganglioma. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.</p></div><div id="CDR0000800108__AboutThis_4"><h3>Reviewers and Updates</h3><p id="CDR0000800108__AboutThis_5">This summary is reviewed regularly and updated as necessary by the <a href="https://www.cancer.gov/publications/pdq/editorial-boards/pediatric-treatment" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PDQ Pediatric Treatment Editorial Board</a>, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).</p><p id="CDR0000800108__AboutThis_22"> Board members review recently published articles each month to determine whether an article should:</p><ul id="CDR0000800108__AboutThis_6"><li class="half_rhythm"><div>be discussed at a meeting,</div></li><li class="half_rhythm"><div>be cited with text, or</div></li><li class="half_rhythm"><div>replace or update an existing article that is already cited.</div></li></ul><p id="CDR0000800108__AboutThis_7">Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.</p><p>The lead reviewers for Childhood Pheochromocytoma and Paraganglioma Treatment are:</p><ul><li class="half_rhythm"><div>Denise Adams, MD (Children's Hospital Boston)</div></li><li class="half_rhythm"><div>Karen J. Marcus, MD, FACR (Dana-Farber of Boston Children's Cancer Center and Blood Disorders Harvard Medical School)</div></li><li class="half_rhythm"><div>William H. Meyer, MD</div></li><li class="half_rhythm"><div>Paul A. Meyers, MD (Memorial Sloan-Kettering Cancer Center)</div></li><li class="half_rhythm"><div>Thomas A. Olson, MD (Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta - Egleston Campus)</div></li><li class="half_rhythm"><div>Alberto S. Pappo, MD (St. Jude Children's Research Hospital)</div></li><li class="half_rhythm"><div>D. Williams Parsons, MD, PhD (Texas Children's Hospital)</div></li><li class="half_rhythm"><div>Arthur Kim Ritchey, MD (Children's Hospital of Pittsburgh of UPMC)</div></li><li class="half_rhythm"><div>Carlos Rodriguez-Galindo, MD (St. Jude Children's Research Hospital)</div></li><li class="half_rhythm"><div>Stephen J. Shochat, MD (St. Jude Children's Research Hospital)</div></li></ul><p id="CDR0000800108__AboutThis_9">Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's <a href="https://www.cancer.gov/contact/email-us" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Email Us</a>. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.</p></div><div id="CDR0000800108__AboutThis_10"><h3>Levels of Evidence</h3><p id="CDR0000800108__AboutThis_11">Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a <a href="/books/n/pdqcis/CDR0000062796/?report=reader">formal evidence ranking system</a> in developing its level-of-evidence designations.</p></div><div id="CDR0000800108__AboutThis_12"><h3>Permission to Use This Summary</h3><p id="CDR0000800108__AboutThis_13">PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”</p><p id="CDR0000800108__AboutThis_14">The preferred citation for this PDQ summary is:</p><p id="CDR0000800108__AboutThis_15">PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Pheochromocytoma and Paraganglioma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: <a href="https://www.cancer.gov/types/pheochromocytoma/hp/child-pheochromocytoma-treatment-pdq" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">https://www.cancer.gov/types/pheochromocytoma/hp/child-pheochromocytoma-treatment-pdq</a>. Accessed <MM/DD/YYYY>. [PMID: 31909942]</p><p id="CDR0000800108__AboutThis_16">Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in <a href="https://visualsonline.cancer.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Visuals Online</a>, a collection of over 2,000 scientific images.
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</p></div><div id="CDR0000800108__AboutThis_17"><h3>Disclaimer</h3><p id="CDR0000800108__AboutThis_18">Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the <a href="https://www.cancer.gov/about-cancer/managing-care" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Managing Cancer Care</a> page.</p></div><div id="CDR0000800108__AboutThis_20"><h3>Contact Us</h3><p id="CDR0000800108__AboutThis_21">More information about contacting us or receiving help with the Cancer.gov website can be found on our <a href="https://www.cancer.gov/contact" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Contact Us for Help</a> page. Questions can also be submitted to Cancer.gov through the website’s <a href="https://www.cancer.gov/contact/email-us" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Email Us</a>.</p></div></div></div></div><div class="fm-sec"><h2 id="_NBK552286_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><p class="contrib-group"><h4>Authors</h4><span itemprop="author">PDQ Pediatric Treatment Editorial Board</span>.</p><h3>Publication History</h3><p class="small">Published online: September 9, 2024.</p><p class="small">Created: <span itemprop="datePublished">December 23, 2019</span>.</p><h3>Version History</h3><ul class="simple-list" style="padding:0"><li><span class="bk_col_itm">NBK552286.10</span> September 9, 2024 (Displayed Version)</li><li><span class="bk_col_itm"><a href="/books/NBK552286.9/?report=reader">NBK552286.9</a></span> January 3, 2024</li><li><span class="bk_col_itm"><a href="/books/NBK552286.8/?report=reader">NBK552286.8</a></span> June 8, 2022</li><li><span class="bk_col_itm"><a href="/books/NBK552286.7/?report=reader">NBK552286.7</a></span> March 2, 2022</li><li><span class="bk_col_itm"><a href="/books/NBK552286.6/?report=reader">NBK552286.6</a></span> December 17, 2021</li><li><span class="bk_col_itm"><a href="/books/NBK552286.5/?report=reader">NBK552286.5</a></span> September 17, 2021</li><li><span class="bk_col_itm"><a href="/books/NBK552286.4/?report=reader">NBK552286.4</a></span> March 12, 2021</li><li><span class="bk_col_itm"><a href="/books/NBK552286.3/?report=reader">NBK552286.3</a></span> February 11, 2021</li><li><span class="bk_col_itm"><a href="/books/NBK552286.2/?report=reader">NBK552286.2</a></span> December 7, 2020</li><li><span class="bk_col_itm"><a href="/books/NBK552286.1/?report=reader">NBK552286.1</a></span> December 23, 2019</li></ul><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright Notice</a></div></div><h3>Publisher</h3><p><a href="http://www.cancer.gov/" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">National Cancer Institute (US)</a>, Bethesda (MD)</p><h3>NLM Citation</h3><p>PDQ Pediatric Treatment Editorial Board. Childhood Pheochromocytoma and Paraganglioma Treatment (PDQ®): Health Professional Version. 2024 Sep 9. In: PDQ Cancer Information Summaries [Internet]. Bethesda (MD): National Cancer Institute (US); 2002-. <span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"></div><div class="small-screen-next"></div></article><article data-type="table-wrap" id="figobCDR00008001082400"><div id="CDR0000800108__2400" class="table"><h3><span class="title">Table 1. Molecular Subgroups of Pheochromocytoma and Paraganglioma</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK552286/table/CDR0000800108__2400/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000800108__2400_lrgtbl__"><table class="no_top_margin"><thead><tr><th colspan="2" rowspan="1" style="vertical-align:top;">Subgroup</th><th colspan="1" rowspan="1" style="vertical-align:top;">Associated Genetic Variants</th><th colspan="1" rowspan="1" style="vertical-align:top;">Germline or Somatic Variants</th></tr></thead><tbody><tr><td colspan="2" rowspan="1" style="vertical-align:top;">Cluster 1:</td><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;"></td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">Cluster 1A</td><td colspan="1" rowspan="1" style="vertical-align:top;"><i>SDHA</i>, <i>SDHB</i>, <i>SDHC</i>, <i>SDHD</i>, <i>FH</i>, <i>MDH2</i>, <i>IDH1</i>, <i>IDH2</i>, <i>GOT2</i>, <i>SLC25A11</i>, and <i>DLST</i></td><td colspan="1" rowspan="1" style="vertical-align:top;">Most are germline</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;"></td><td colspan="1" rowspan="1" style="vertical-align:top;">Cluster 1B</td><td colspan="1" rowspan="1" style="vertical-align:top;"><i>EGLN2</i>, <i>EGLN1</i>, <i>VHL</i>, <i>EPAS1</i>, and <i>ACO1</i></td><td colspan="1" rowspan="1" style="vertical-align:top;">25% are germline</td></tr><tr><td colspan="2" rowspan="1" style="vertical-align:top;">Cluster 2</td><td colspan="1" rowspan="1" style="vertical-align:top;"><i>RET</i>, <i>NF1</i>, <i>HRAS</i>, <i>TMEM127</i>, <i>MAX</i>, and <i>FGFR1</i></td><td colspan="1" rowspan="1" style="vertical-align:top;">20% are germline </td></tr><tr><td colspan="2" rowspan="1" style="vertical-align:top;">Cluster 3</td><td colspan="1" rowspan="1" style="vertical-align:top;"><i>CSDE1</i> and <i>MAML3</i></td><td colspan="1" rowspan="1" style="vertical-align:top;">All are somatic</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobCDR0000800108887"><div id="CDR0000800108__887" class="table"><h3><span class="title">Table 2. Characteristics of Paraganglioma (PGL) and Pheochromocytoma (PCC) Associated With Susceptibility Genes<sup>a</sup></span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK552286/table/CDR0000800108__887/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000800108__887_lrgtbl__"><table class="no_margin"><thead><tr><th colspan="1" rowspan="1" style="vertical-align:top;">Syndrome</th><th colspan="1" rowspan="1" style="vertical-align:top;">Germline Variant </th><th colspan="1" rowspan="1" style="vertical-align:top;">Proportion of all PGL/PCC (%)</th><th colspan="1" rowspan="1" style="vertical-align:top;">Mean Age at Presentation (y)</th><th colspan="1" rowspan="1" style="vertical-align:top;">Penetrance of PGL/PCC (%)</th></tr></thead><tbody><tr><td colspan="1" rowspan="1" style="vertical-align:top;">MEN2
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">
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<i>RET
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</i>
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">5.3
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">35.6
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">50
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</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">VHL</td><td colspan="1" rowspan="1" style="vertical-align:top;">
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<i>VHL</i>
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">9.0</td><td colspan="1" rowspan="1" style="vertical-align:top;">28.6</td><td colspan="1" rowspan="1" style="vertical-align:top;">10–26</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">NF1</td><td colspan="1" rowspan="1" style="vertical-align:top;">
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<i>NF1</i>
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">2.9</td><td colspan="1" rowspan="1" style="vertical-align:top;">
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41.6</td><td colspan="1" rowspan="1" style="vertical-align:top;">0.1–5.7</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">PGL1</td><td colspan="1" rowspan="1" style="vertical-align:top;">
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<i>SDHD</i>
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">7.1</td><td colspan="1" rowspan="1" style="vertical-align:top;">
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35.0</td><td colspan="1" rowspan="1" style="vertical-align:top;">86</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">PGL2</td><td colspan="1" rowspan="1" style="vertical-align:top;">
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<i>SDHAF2</i>
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</td><td colspan="1" rowspan="1" style="vertical-align:top;"><1</td><td colspan="1" rowspan="1" style="vertical-align:top;">
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32.2</td><td colspan="1" rowspan="1" style="vertical-align:top;">100</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">
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PGL3
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">
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<i>SDHC</i>
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</td><td colspan="1" rowspan="1" style="vertical-align:top;"><1</td><td colspan="1" rowspan="1" style="vertical-align:top;">42.7</td><td colspan="1" rowspan="1" style="vertical-align:top;">Unknown</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">PGL4</td><td colspan="1" rowspan="1" style="vertical-align:top;">
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<i>SDHB</i>
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">
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5.5</td><td colspan="1" rowspan="1" style="vertical-align:top;">32.7</td><td colspan="1" rowspan="1" style="vertical-align:top;">77</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">-</td><td colspan="1" rowspan="1" style="vertical-align:top;">
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<i>SDHA</i>
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</td><td colspan="1" rowspan="1" style="vertical-align:top;"><3</td><td colspan="1" rowspan="1" style="vertical-align:top;">40.0</td><td colspan="1" rowspan="1" style="vertical-align:top;">Unknown
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|
</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">
|
|
-
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|
</td><td colspan="1" rowspan="1" style="vertical-align:top;">
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<i>KIF1B</i>
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</td><td colspan="1" rowspan="1" style="vertical-align:top;"><1</td><td colspan="1" rowspan="1" style="vertical-align:top;">46.0</td><td colspan="1" rowspan="1" style="vertical-align:top;">Unknown</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">-
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|
</td><td colspan="1" rowspan="1" style="vertical-align:top;">
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|
<i>EGLN1</i>
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</td><td colspan="1" rowspan="1" style="vertical-align:top;"><1</td><td colspan="1" rowspan="1" style="vertical-align:top;">
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43.0</td><td colspan="1" rowspan="1" style="vertical-align:top;">
|
|
Unknown</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">-
|
|
</td><td colspan="1" rowspan="1" style="vertical-align:top;">
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|
<i>TMEM127</i>
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|
</td><td colspan="1" rowspan="1" style="vertical-align:top;"><2
|
|
</td><td colspan="1" rowspan="1" style="vertical-align:top;">
|
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42.8</td><td colspan="1" rowspan="1" style="vertical-align:top;">
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|
Unknown</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">-</td><td colspan="1" rowspan="1" style="vertical-align:top;">
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<i>MAX</i> [<a class="bibr" href="#CDR0000800108_rl_865_4" rid="CDR0000800108_rl_865_4">4</a>]</td><td colspan="1" rowspan="1" style="vertical-align:top;"><2</td><td colspan="1" rowspan="1" style="vertical-align:top;">34 </td><td colspan="1" rowspan="1" style="vertical-align:top;">Unknown</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Carney triad</td><td colspan="1" rowspan="1" style="vertical-align:top;">Unknown</td><td colspan="1" rowspan="1" style="vertical-align:top;"><1</td><td colspan="1" rowspan="1" style="vertical-align:top;">27.5
|
|
</td><td colspan="1" rowspan="1" style="vertical-align:top;">-</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Carney-Stratakis</td><td colspan="1" rowspan="1" style="vertical-align:top;">
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<i>SDHB, C, D</i>
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|
</td><td colspan="1" rowspan="1" style="vertical-align:top;"><1</td><td colspan="1" rowspan="1" style="vertical-align:top;">33</td><td colspan="1" rowspan="1" style="vertical-align:top;">Unknown</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">MEN1</td><td colspan="1" rowspan="1" style="vertical-align:top;">
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|
<i>MEN1</i>
|
|
</td><td colspan="1" rowspan="1" style="vertical-align:top;"><1</td><td colspan="1" rowspan="1" style="vertical-align:top;">30.5</td><td colspan="1" rowspan="1" style="vertical-align:top;">Unknown</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Sporadic disease</td><td colspan="1" rowspan="1" style="vertical-align:top;">
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No variant
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">70
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|
</td><td colspan="1" rowspan="1" style="vertical-align:top;">48.3</td><td colspan="1" rowspan="1" style="vertical-align:top;">-</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">MEN1 = multiple endocrine neoplasia type 1; MEN2 = multiple endocrine neoplasia type 2; NF1 = neurofibromatosis type 1; VHL = von Hippel-Lindau disease.</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin"><sup>a</sup>Adapted from Welander et al.[<a class="bibr" href="#CDR0000800108_rl_865_1" rid="CDR0000800108_rl_865_1">1</a>]</p></div></dd></dl></dl></div></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script></div></div>
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